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Blood. 2019 Oct 24. pii: blood.2019002220. doi: 10.1182/blood.2019002220. [Epub ahead of print]

Therapy-induced mutations drive the genomic landscape of relapsed acute lymphoblastic leukemia.

Author information

1
Key Laboratory of Pediatric Hematology and Oncology Ministry of Health.
2
St. Jude Children's Research Hospital, Memphis, Tennessee, United States.
3
St Jude Children's Research Hospital, Memphis, Tennessee, United States.
4
Shanghai Children's Medical Center, Shanghai, China.
5
State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Tianjin, China.
6
St. Jude Children's Research Hospital.
7
Pediatric Translational Medicine Institute, Shanghai, China.
8
Second Hospital of Anhui Medical University, Hefei, Alabama, China.
9
Princeton University, Princeton, New Jersey, United States.
10
Shanghai Children's Medical Center.
11
Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Shanghai, China.
12
Guangzhou Women and Children's Medical Center, Guangzhou, China.
13
WuXi NextCODE Co., Ltd., Shanghai, China.
14
Shanghai Jiao Tong University School of Medicine.
15
Chinese Academy of Medical Sciences, Beijing Union Medical College, Institute of Hematology.
16
Chinese Academy of Medical Sciences, Beijing Union Medical College, Institute of Hematology, Tianjin, China.
17
shanghai children's medical center, Shanghai, China.
18
University of California, San Diego, La Jolla, La Jolla, California, United States.

Abstract

To study the mechanisms of relapse in acute lymphoblastic leukemia (ALL), we performed whole-genome sequencing of 103 diagnosis-relapse-germline trios and ultra-deep sequencing of 208 serial samples in 16 patients. Relapse-specific somatic alterations were enriched in 12 genes (NR3C1, NR3C2, TP53, NT5C2, FPGS, CREBBP, MSH2, MSH6, PMS2, WHSC1, PRPS1, and PRPS2) involved in drug response. Their prevalence was 17% in very early relapse (<9 months from diagnosis), 65% in early relapse (9-36 months), and 32% in late relapse (>36 months) groups. Convergent evolution, where multiple subclones harbor mutations in the same drug resistance gene, was observed in six relapses and confirmed by single-cell sequencing in one case. Mathematical modeling and mutational signature analysis indicated that early relapse resistance acquisition was frequently two-step process where a persistent clone survived initial therapy, and later acquired bona fide resistance mutations during therapy. In contrast, very early relapses arose from pre-existing resistant clone(s). Two novel relapse-specific mutational signatures, one of which was caused by thiopurine treatment based on in vitro drug exposure experiments, were identified in early and late relapses but were absent from 2,540 pan-cancer diagnosis samples and 129 non-ALL relapses. The novel signatures were detected in 27% of relapsed ALLs and were responsible for 46% of acquired resistance mutations in NT5C2, PRPS1, NR3C1, and TP53. These results suggest that chemotherapy-induced drug resistance mutations facilitate a subset of pediatric ALL relapses.

PMID:
31697823
DOI:
10.1182/blood.2019002220

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